As the building blocks of peptides and proteins, α-amino acids are important targets for the medicinal and biotechnology fields and their optical purity is an important factor in biological activity. Natural and non-natural (also known as non-proteinogenic) amino acids have wide utility in synthetic and medicinal chemistry, with diverse roles as chiral auxiliaries, ligands for catalysis, starting materials for natural product syntheses and for incorporation into drugs. The latter role is particularly important for non-natural amino acids, as they will often be poorly recognized by protease enzymes, conferring greater in vivo
stability on the molecule.
In the late 1970’s Schöllkopf developed a chiral auxiliary based method to produce optically pure α-amino acids via diastereoselective alkylation of a masked glycine. The methodology entails the cyclisation of a chiral α-amino acid with glycine to yield a bis-lactam, which is converted to a bis-lactim ether by treatment with Meerwein’s salt (trimethyloxonium tetrafluoroborate).
The robustness and versatility of the Schöllkopf methodology, and the ready availability of both ( R )-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine (product code FD04039) and ( S )-2,5Dihydro-3,6-dimethoxy-2-isopropylpyrazine auxiliaries (product code FD03725) allow this method of synthesis of α-amino acid acids to compare favourably to other classical approaches such as the Strecker synthesis or the asymmetric hydrogenation of dehydroamino acids.
The methodology continues to find widespread use in medicinal chemistry, for example in the recent synthesis of a series of anthranilimide inhibitors of glycogen phosphorylase with the potential to treat Type 2 diabetes.